16-methyl-Δ1,4-pregnadiene-3,20-dione

ABSTRACT

A compound of the formula ##STR1## in which ##STR2## is either a 3-keto-Δ4-system or a 3-keto -Δ1,4-system or a 3-OR 4  - Δ5-system in which R 4  is hydrogen or a protector group of hydroxy, R is methyl --CH 2  OH or --CH 2  OR&#39;, in which R&#39; is a protector group of hydroxy, R 1  and R&#39; 1  are individually selected from the group consisting of methyl, a branched alkyl not possessing hydrogen in the β position of 5 to 8 carbon atoms, aryl of up to 10 carbon atoms, heteroaryl of up to 10 carbon atoms and at least one heteroatom chosen from nitrogen, sulfur and oxygen and benzyl, n and m, are individually numbers 0 or 1, R 2  and R 3  are hydrogen or R 2  is fluorine and R 3  is formyloxy or acetyloxy and the dotted lines in position 9(11) indicate the optional presence of a second bond which is useful for the preparation of compounds of formula A.

This application is a division of U.S. patent application Ser. No.07/903,886, filed Jun. 25, 1992, now U.S. Pat. No. 5,248,773.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and a novel process and intermediates for their preparation.

It is another object of the invention to provide a novel process for thepreparation of compounds of formula A.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention have the formula ##STR3## in which##STR4## is either a 3-keto-Δ4-system or a 3-keto -Δ1,4-system or a3-OR₄ -Δ5-system in which R₄ is hydrogen or a protector group ofhydroxy, R methyl, --CH₂ OH or --CH₂ --OR', in which R' is a protectorgroup of hydroxy, R₁ and R' are individually selected from the groupconsisting of methyl, a branched alkyl not possessing hydrogen in the βposition of 5 to 8 carbon atoms, aryl of up to 10 carbon atoms,heteroaryl of up to 10 carbon atoms and at least one heteroatom chosenfrom nitrogen, sulfur and oxygen and benzyl, n and m, are individuallynumbers 0 or 1, R₂ and R₃ are hydrogen or R₂ is fluorine and R₃ isformyloxy or acetyloxy and the dotted lines in position 9(11) indicatesthe optional presence of a second bond.

R' is preferably a alkyl of 1 to 6 carbon atoms such as ethyl, ethyl,propyl, isopropyl, butyl, isobutyl and tert-butyl, acyl of 1 to 6 carbonatoms such as formyl, acetyl, propionyl, butyryl and pivaloyl, aralkylsuch as benzyl, tetrahydropyrannyl, an alkyl, aryl or arylalkyl silyl,preferably trimethyl silyl, tert-butyl dimethyl silyl, triphenyl silylor diphenyl tert-butyl silyl. The above list of values of R' is notlimitative and any protector group of the hydroxy known to a man skilledin the art, compatible with the operating conditions of the processdefined above, is suitable.

When R'₁ and R' are alkyl of 5 to 8 carbon atoms, it is preferablyneopentyl or a similar higher alkyl not possessing a hydrogen atom inthe β-position When R₁ and R'₁ are aryl it is preferably phenyl, phenylsubstituted by one or two methyls or naphthyl When R₁ and R'₁ areheteroaryl it is preferably pyridyl, thiazolyl, or benzothiazolyl.benzothiazolyl.

When R₄ is a protector group of hydroxy, it is notably one of the groupsmentioned above for R'.

Among the preferred products of formula I are those of the formula##STR5## in which R, R₁, R'₁, R₂, R₃, m and n have the above meaningsand the dotted lines in position 1(2) and 9(11) symbolize the optionalpresence of a second bond.

Among the preferred compounds of formula I are those wherein R ismethyl, --CH₂ OH or --CH₂ OR" in which R" is alkyl of 1 to 4 carbonatoms, acyl of 1 to 5 carbon atoms or benzyl, R₁ and R'₁ areindividually methyl, phenyl, tolyl or benzyl and n, m, R₂, R₃ and thedotted lines are defined as above.

Among the compounds of formula I are those of the formula ##STR6## inwhich K, R, R₁, R'₁, R₂, R₃ and the dotted lines are defined aspreviously, the compounds of the formula ##STR7## in which K, R, R₁,R'₁, R₂, R₃ and the dotted lines are defined as previously and thecompounds of the formula ##STR8## in which K, R, R₁, R'₁, R₂, R₃ and thedotted lines are defined as previously.

Among the preferred compounds of formula I are those wherein ##STR9## isa 3-keto-Δ1,4-system and R is --CH₂ --OR", R" being defined aspreviously, R₂ and R₃ are hydrogen and the dotted lines in position9(11) are a second bond.

Specific preferred compounds of formula I are21-acetoxy-16α-[bis(phenylthio)-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione;21-acetoxy-16α-[(phenylthio) (phenylsulfinyl)-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione and21-acetoxy-16α-[bis(phenylsulfinyl)methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione.

The novel process of the invention for the preparation of a compound offormula I comprises reacting a compound of the formula ##STR10## inwhich K, R, R₂, R₃ and the dotted lines have the above meanings in abasic medium with a reagent of the formula

    R.sub.1 S--CH.sub.2 --NO.sub.2

in which R₁ has the above meaning to obtain a compound of the formula##STR11## in which K, R, R₁, R₂, R₃ and the dotted lines have the abovemeanings reacting the latter in the presence of an acid, with a thiol orthiophenyl of the formula

    HS--R'.sub.1

in which R'₁ has the above meaning to obtain a compound of the formula##STR12## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lines have theabove meanings optionally reacting the latter with an equivalent of anoxidizing agent to obtain a compound of the formula ##STR13## in whichK, R, R₁, R'₁, R₂, R₃ and the dotted lines have the above meanings, orwith at least two equivalents of an oxidizing agent to obtain a compoundof the formula ##STR14## in which K, R, R₁, R'₁, R₂, R₃ and the dottedlines have the above meanings.

A preferred mode of the process for preparing a compound of formula Icomprises reacting a compound of the formula ##STR15## in which K, R,R₂, R₃ and the dotted lines have the above meanings in a basic mediumwith a reagent of the formula

    R.sub.1 S--CH.sub.2 --NO.sub.2

in which R₁ has the above meaning to obtain a compound of the formula##STR16## in which K, R, R₁, R₂, R₃ and the dotted lines have the abovemeanings and reacting the latter in the presence of an acid with a thiolor a thiophenol of the formula

    HS--R'.sub.1

in which R'₁ has the above meaning to obtain a compound of the formula##STR17## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lines have theabove meanings and reacting the latter with at least two equivalents ofan oxidizing agent to obtain a compound of the formula ##STR18## inwhich K, R, R₁, R'₁, R₂, R₃ and the dotted lines have the abovemeanings.

The action of the reagent of formula P with the compound of formula IIis carried out in the presence of a base which can be an amino base suchas a secondary or tertiary amine like diethylamine or triethylamine,diazabicycloundecene (DBU), diazabicyclononene (DBN), an acetate, acarbonate, a hydride, a hydroxide or an alkali metal alkoxide, thestrong base being used preferably in a catalytic quantity.

The operation is carried out in an organic solvent such as an ether liketetrahydrofuran or dioxane, an alcohol like methanol or ethanol, anaromatic solvent like benzene or toluene, or dimethylformamide,dimethylsulfoxide or methylene chloride.

The action of the thiol or the thiophenol is catalyzed by an acid,preferbly a weak acid, which can be a carboxylic acid such as formicacid, acetic acid or propionic acid, a Lewis acid such as zinc chlorideor aluminum chloride, or also phosphoric acid. The said acid can also,if desired, be used as the solvent. The solvent can also be an aromaticsolvent such as benzene or toluene. The reaction conditions are chosenif appropriate so that they are compatible with the protector group ofthe hydroxy that can be carried by compound II and, more generally, withthe structure of the molecule which one wishes to preserve. This isknown to a man skilled in the art.

The oxidizing agent used to convert the compound of formula I_(A) intothe monosulfoxide or into the disulfoxide can be a peracid such asm-chloro perbenzoic acid, perbenzoic acid, perphthalic acid, themagnesium salt of monoperphthalic acid, or hydrogen peroxide in thepresence of a carboxylic acid such as acetic acid, or a periodate, aperborate or a persulfate, preferably of sodium or potassium.

Also an object of the invention, as new industrial compounds are thecompounds of formula III, as defined above.

The novel process of the invention for the preparation of a compound ofthe formula ##STR19## in which K, R, R₂, R₃ and the dotted lines havethe above meanings comprises reacting a compound of formula I_(A) withat least two equivalents of an oxidizing agent to obtain a compound offormula I_(C) and reacting the latter hot with a thiophilic agent toobtain the expected compound of formula A or subjecting a compound offormula I_(C) hot with a thiophilic agent to obtain the expectedcompound of formula A.

In a variation of the process to obtain a compound of formula A acompound of formula I_(B) is heated optionally in the presence of athiophilic agent to obtain a compound of the formula ##STR20## in whichK, R, R'₁, R₂, R₃ and the dotted lines have the above meanings and thedotted line in position 16(17) and 16(16') symbolizes the existence of avinyl and allyl sulfide mixture and the wavy line symbolizes theexistence of a mixture of isomers, reacting the latter with at least oneequivalent of an oxidizing agent to obtain a compound of the formula##STR21## in which K, R, R'₁, R₂, R₃, the dotted lines and the wavy linehave the above meanings and reacting the latter hot with a thiophilicagent to obtain the expected compound of formula A.

It is not necessary to isolate the disulfoxide of formula I_(C) and afirst --S[O]R₁ group can be removed therefrom by heating only to obtainthe monosulfoxide of formula V and the second group can be removed bythe sulfenate by hot reaction with a thiophilic agent to obtain themonosulfoxide of formula V with or without isolation. The compound offormula I_(B) can be heated to eliminate the --S[O]R₁ and the compoundof formula IV can be oxidized to form the compound of formula V.

The oxidizing agent used to convert the compound of formula I_(A) into acompound of formula I_(C), or to convert the compound of formula IV to acompound of formula V is one of those which have been mentioned above.

The thiophilic agent can be triphenylphosphine, trimethyl- ortriethylphosphine, triphenyl-, trimethyl- or triethylphosphite,dimethyl- or diethylphosphite, a secondary amine such as diethylamine,phosphorous acid, a thiol such as thiophenol or methyl mercaptan, or athiosulfate, or a bisulfite, for example of sodium. Triphenylphosphineis particularly preferred.

The operation is carried out in an organic solvent or an organic solventmixture, preferably at reflux. Examples of aromatic solvents arebenzene, toluene, xylene, cyclohexane, tetrahydrofuran, dioxane,dimethoxyethane, monoglyme or diglyme, if appropriate mixed with aprotic solvent, notably an alcohol such as methanol, ethanol orisopropanol.

The operation is carried out optionally in the presence of an alkalinecarbonate such as sodium carbonate or calcium carbonate.

In the process of the invention, it is likely that during the process,the allyl form of the sulfoxide of formula V is found in equilibriumwith the sulfenate form V_(a) : ##STR22## which undergoes a reduction toproduce the desired compound (A).

In a preferred mode of the process, a compound of formula I_(A) isreacted with at least two equivalents of an oxidizing agent to obtain acompound of formula I_(C) and reacting the latter hot with a thiophilicagent to obtain the expected compound of formula A.

In another preferred mode of the process, a compound of formula I_(C) isreacted hot with a thiophilic agent to obtain the desired compound offormula A.

It is possible to deprotect the products containing one or two protectedhydroxys by using methods known to a man skilled in the art.

The novel industrial compounds useful as intermediates are the compoundsof formula IV, as well as the compounds of the formula ##STR23## and thecompounds of the formula ##STR24## with the exception of those in whichR is methyl, R₂ and R₃ are hydrogen and a double bond is present inposition 9(11).

The compounds of formula A in which R is methyl are described in U.S.Pat. Nos. 3,354,184; 3,178,462; 3,312,692; 3,359,287; 3,064,015; and3,519,619 or can be obtained from the compounds described in thesePatents by known processes. Those in which R is free or protected --CH₂OH are themselves described for example in the German Patents No.1,263,765; No. 1,263,766, U.S. Pat. Nos. 3,350,394; 4,567,001;3,354,184, French Patent No. 1,285,336 and European Patents No. 104,054or No. 174,496, or can be obtained by known processes from compoundsdescribed in these Patents and U.S. Pat. Nos. 3,309,272 or 3,178,462.

The compounds of formula A are useful as intermediates in the synthesisof therapeutically active compounds.

The compounds of formula II in which R is methyl are described in U.S.Pat. Nos. 2,705,719; 2,817,671, French Patent No. 1,058,850; BelgianPatent No. 711,016 or English Patents No. 881,501; No. 2,199,325 or canbe obtained from compounds described in these Patents, as well as in theGerman Patent No. 2,207,420 or U.S. Pat. Nos. 4,113,722 and 3,976,638,by processes known to a man skilled in the art. The compounds of formulaII in which R is free or protected --CH₂ OH are described in U.S. Pat.Nos. 2,802,839; 2,745,852; 2,773,058; 2,864,834; Belgian Patents No.540,478 or No. 789,387; German Patent No. 2,207,420; Dutch Patent No6,902,507 or Russian Patent No 819,119, or can be obtained from thecompounds described in these Patents, as well as in U.S. Pat. Nos.3,976,638 or 2,966,504; European Patent No. 123,736 or Canadian PatentNo. 760,431, by processes known to a man skilled in the art.

The reagents of formula P in which R₁ is methyl and phenyl are describedin J. Chem. Soc. Chem. Comm. 1983, 835, 1978, 362 or also J. Org. Chem.1978, Vol. 43, p. 3101. The other reagents of formula P can be preparedby similar methods to those described in the above references.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 121-acetoxy-16α-[bis-(phenylthio)-methyl]-Δ1,4,9911)-pregnatriene-3,20-dioneSTEP A:21-acetoxy-16α-[(phenylthio)-nitro-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione

2.01 g of 21-acetoxy-Δ1,4,9(11)-16-pregnatetraen-3,20-dione and 1.1 g of(phenylthio)-nitro-methane were dissolved under inert atmosphere and inthe shade in a mixture of 20 ml of dry THF and 20 ml of tert-butanol.0.8 ml of DBU (1,8-diazabicyclo[5,4,0]undec-7ene) were added and thereaction mixture was stirred at ambient temperature for 8 hours. Asolution of 2 g of citric acid in 50 ml of water was added and afterextraction with dichloromethane, filtering through silica, and dryingover sodium sulfate, the solvent was filtered and evaporated underreduced pressure to obtain 3.73 g of crude product. The excess(phenylthio)-nitromethane was eliminated by taking up the crude reactionproduct in a pentane (75 ml)-ether (30 ml) mixture to obtain 2.79 g of21-acetoxy-16α-[(phenylthio) -nitro-methyl]-Δ1,4,9(11)-pregnatrien-3,20-dione melting at 92° to 100° C.

IR Spectrum (cm⁻¹):

1740(s); 1720(s); 1655(s); 1615(w); 1595(w); 1540(s): (No₂); 885 (w)(C-SPh)

NMR Spectrum ¹ H:

2 visible isomers: 0.72 and 0.73 (3H,s,Me-18); 1.41 (3H,s,Me-19); 2.17and 2.20 (3H,s,COCH₃); 2.67 and 2.97 (1H, d, J=9.2 Hz,c17-H); 3.60(1H,m,W_(1/2) =35Hz, C₁₆ -H); 4.43 and 4.75 (2H, AB system, J=16,9Hz)and 4.58 and 4.88 (2H, AB system, J=17,0 Hz); 5.38 (1H,d,J=8,14 Hz, C₁₆'-H) and 5.43 (1H,d,J=5,9 Hz, C₁₆ '-H); 5.55(1H,massive, W_(1/2) =10 Hz,C₁₁ -H); 6.08 (1H, massive, W_(1/2) =10 Hz, C₄ -H); 6.30 (1H, d-d,J=10,2 Hz, J=1.7 Hz, C₂ -H); 7.17 (1H,d,J=10,2 Hz, C₁ -H), 7.34- 7.48(5H, massive).

NMR Spectrum ⁻⁻ C:

30 carbons, 2 isomers: even: 29.87 and 30.65 (s); 32.00(s): 34.60(s);44.38 and 44.60 (q); 45.91(q); 69.01(s); 130.58(q); 143.21 and143.34(q); 166.03(q); 170.40(q); 186.24(q); 201.40 and 201.65(q). odd:13.64(p, 18-Me); 20.52 (p, COCH₃); 26.61 (p, 19-Me); 36.29(t); 40.05 and40.17 (t); 40.97 (t); 52.21 and 52.62 (t); 61.95 (t); 98.03 and98.54(t); 119.65(t); 124.18(t); 127.62(t); 129.71(t); 129.87(t);132.94(t); 133.23(t); 154.17(t).

Mass Spectrum:

m/z=512(M+); 483; 391; 314; 213.

STEP B:21-acetoxy-16α-[bis(phenylthio)-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione

2 ml of thiophenol and 5 ml of acetic acid were mixed together and takento boiling point under a nitrogen atmosphere. 2.51 g of21-acetoxy-16α-[(phenylthio) -nitro-methyl]-Δ1,4,9(11) -pregnatrien-3,20-dione were added and the mixture was refluxed for 4 hours 30minutes. Once the mixture had cooled down, 25 ml of ether were added.After neutralization of the acetic acid by a saturated solution ofsodium bicarbonate, 25 ml of ether were added. The organic phase waswashed with water, then dried and concentrated to obtain 4 g of a brownoil. The excess thiophenol was eliminated by taking up the crudereaction product in 25 ml of ether and 100 ml of pentane to obtain 1.70g of the expected disulfide derivative melting at 98°-100° C. afterpurification by chromatography on silica (eluant: ether-dichloromethane9-1) and having a specific rotation of [α]_(D) =-13.4° (C=12.7 mg/ml inchloroform).

IR Spectrum (cm⁻¹):

1750(s); 1720(s); 1665(s); 1630(m); 1610w); 1585(w); 1550(w); 1480(w);1440(w); 1410(w); 1370(w); 1270(w); 1120(w); 1155(w); 1070(m); 1050(m);1025 (m); 890(m).

NMR Spectrum ¹ H:

0.61(3H,s,Me-18); 1.37(3H,s,Me-19); 2.10(3H,s, COCH₃); 2.87(1H,d,J=9,2Hz, C₁₇ -H); 3.31(1H,m,W_(1/2) =19 Hz, C₁₆ '-H); 4.25 and 4.68(2H,AB system,J=16.9 Hz); 4.33(1H,d,J=4.8 Hz, C_(16') -H); 5.47 (1H,massive, W_(1/2) =9 Hz (C₁₁ -H); 6.03(1H,massive, W_(1/2) =5 Hz, C₄ -H);6.23(1H,d-d, J=10, 1 Hz, J=1.7 Hz, C₂ -H); 7.10(1H,d,J=10,2 Hz, C₁ -H),7.18-7.41(10H, massive).

NMR Spectrum ⁻⁻ C:

even: 30.86 (s); 32.14 (s); 34.64 (s); 40.23 (s); 44.54(q); 134.40(q);143.38(q); 154.45(q); 166.50(q); 170.32(q); 186.31(q); 202.50(q).

odd: 13.81(p); 20.53(p); 26.61(p); 36.50(t); 43.52(t); 45.98(t);52.75(t); 62.47(t); 64.64(t); 69.09(t); 119.89(t); 124.03(t); 127.49(t);127.88(t); 127.97(t); 129.16(t); 132.27(t); 132.57(t).

Mass Spectrum: m/z=489 (M+-Sph).

EXAMPLE 221-acetoxy-16α[(phenylthio)-(phenyl-sulfinyl)-methyl]-Δ1,49(11)-pregnatriene-3,20-dione

60 mg of the disulfide of Example 1 were dissolved in 1 ml ofdichloromethane and the mixture was cooled to -60° C. 26 mg ofmeta-chloroperbenzoic acid were added and after one hour, another 5 mgof metachloroperbenzoic acid were added. The reaction mixture stood at-60° C. for 1 hour and then 2 ml of a saturated solution of sodiumbicarbonate were added. The mixture returned to ambient temperature andwas extracted with dichloromethane (2×1.5 ml). The organic phase waswashed with water (3×2 ml), then dried and the solvent was evaporatedunder reduced pressure to obtain 56 mg of the expected crudemonosulfoxide. This derivative was unstable and was kept in arefrigerator.

EXAMPLE 321-acetoxy-16α-[bis(phenylsulfinyl)-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione

1.09 g of the product of Example 1 were dissolved in 10 ml ofdichloromethane and cooled to -78° C. 796 mg of meta chloroperbenzoicacid at 80% were added and the reaction mixture was held at -78° C for 3hours. 15 ml of a saturated solution of sodium bicarbonate were addedand the mixture was immediately taken to ambient temperature andextracted with dichloromethane. The organic phase was washed with water,dried and the solvent was evaporated under reduced pressure. Thedisulfoxide obtained was purified by chromatography on silica (eluant:cyclohexane: ethyl acetate 1/1) to obtain 649 mg of the expectedcompound.

IR Spectrum (cm⁻¹):

3050, 2960, 2920, 1745(s), 1720(s), 1660(s), 1625, 1615(m), 1580,1450(m), 1375, 1320, 1270, 1240(s), 1150(m), 1090(m), 1050(m), 890.

NMR Spectrum ¹ H:

1st isomer: 0.62 (3H,s,Me-18); 1.40 (3H,s,Me-19); 2.18 (3H,s, COCH₃);3.43-3.54 (3H,16-H,16'-H and 17-H); 4.29 and 4.59 (2H,AB system, J=16.6Hz); 5.51 (1H,massive, W_(1/2) =10 Hz, C₁₁ -H); 6.08 (1H,massive,W_(1/2) =5 Hz, C₄ -H); 6.28 (1H,d-d,J=10.2 Hz, J=1.7 Hz, C₂ -H); 7.15(1H,d, J=10, 1 Hz, C₁ H), 7.31-7.66 (10H, massive).

2nd isomer: 0.68(3H,s,Me-18); 1.40(3H,s,Me-19); 2.13(3H,s,COCH₃);3.54-3.62(3H,16H, 16'-H and 17-H); 4.44 and 4.79(2H,AB system, J=16.5Hz); 5.58(1H, massive, W_(1/2) =10 Hz,C₁₁ -H); 6.08 (1H,massive, W_(1/2)=5 Hz,C₄ -H); 6.28(1H,dd,J=10.2 Hz, J=1.7 Hz,C₂ -H); 7.18 (1H,d, J=10.1Hz,C₁ -H); 7.31-7.66(10H, massive).

EXAMPLE 3 21-acetoxy-16α-[(phenylthio)-(phenylsulfinyl)]and 6α-[bis(phenylsulfinyl)-methyl]-Δ1,4,9(11)-pregnatriene-3,20-dione

0.206 g of the disulfide of Example 1 were diluted with 2 ml of aceticacid under an argon atmosphere and the mixture was cooled to 0° C. usingan ice bath. 5 drops of 30% hydrogen peroxide were added to the mixtureand a few drops of dichloromethane were added. The mixture stood toallow the temperature to rise and after 21 hours at ambient temperature,a majority of the monosulfoxide was obtained which was identified bycomparison with the product of Example 2. The reaction was continued forapproximately 50 hours under an inert atmosphere and at ambienttemperature, then stopped by the addition of water. After treatment asin Example 3, the expected disulfoxide was obtained which was identicalto that of Example 3.

EXAMPLE 4 21-acetoxy-16-methylene-Δ1,4,9(11)-pregnatriene-17α-ol3,20-dione STEP A:21-acetoxy-16α-[(phenylthio)-methyl)]-Δ1,4,9(11)-16-pregnatetraene-3,20-dioneand the corresponding 16α-[(phenylthio)-methylene]derivative

The monosulfoxide of Example 2 from 204 mg of disulfide was taken up in3 ml of dry toluene. 101 mg of triphenylphosphine were added and thesolution was refluxed under an argon atmosphere for 15 hours. Afterheating for 6 hours, 55 mg of triphenylphosphine were added and thetoluene was evaporated off. The product was purified by chromatographyon silica (eluant: cyclohexane/ethyl acetate 9/1 then 3/1) to obtain 143mg of a mixture of two isomers of the position for the double bond inposition 16 (Δ16-16' or Δ16-17).

IR Spectrum (cm⁻¹): 3020, 2910, 2820, 1750(s), 1720(m), 1660(s),1620(m), 1580, 1550, 1430, 1370, 1260, 1040, 880.

NMR Spectrum ¹ H:

0.80(3H,s,Me-18); 1.41 and 1.42(3H,s,Me-19); 2.18 and 2.19(3H,s, COCH₃);3.38(1H,m,W_(1/2) =10 Hz, C₁₇ -H); 3.72 and 4.09 (2H,AB system, J=13.6Hz,C_(16') -H.sub.); 4.44 and 4.67(2H,AB system, J=16.6 Hz) and 4.71 and4.90 (2H,AB system, J=17 Hz); 5.50 and 5.59 (1H,massive,W_(1/2) =12.5Hz, C₁₁ -H); 6.09(1H,massive, W_(1/2) =5 Hz,C₄ -H); 6 30(1H,d-d, J=10.2Hz, J=1.7 Hz,C₂ -H); 6.31 and 6.27(1H,d,J=1.9 Hz, C₁₆ '-H) , 7.16-7.52(6H, massive).

NMR Spectrum ¹³ C:

even: 32.03; 34.27; 34.66; 36.66; 37.12; 37.77; 40.41; 44.05; 45.97;47.09; 68.08; 69.01; 134.58; 136.18; 143.06; 143.79; 144.11; 145.90;151.58; 166.37; 170.29; 186.34; 193.57; 200.77.

odd: 14.16; 16.02; 20.53; 26.54; 28.72; 35.73; 51.19; 63.20; 117.37;119.84; 120.23; 123.97; 126.43; 127.43; 128.54; 129.02; 129.09; 131.72;154.47.

Mass Spectrum:

m/z=490, 489, 488(M+), 448, 447, 446(M+-COCH₃), 430, 415, 387, 319, 207.

STEP B:21-acetoxy-16α-[(phenylsulfinyl)-methyl]-Δ1,4,9(11)-16-pregnatetraene-3,20-dioneand the corresponding 16α-[(phenylsulfinyl)-methylene]derivative

6.42 g of the mixture of isomers of Step A were dissolved in 100 ml ofdichloromethane and the mixture was cooled to -78° C. under a nitrogenatmosphere. 2.92 g of metachloroperbenzoic acid at 80% were added andthe mixture was stirred for approximately 2 hours. The mixture wastreated at low temperature with a saturated solution of sodiumbicarbonate, then with water, followed by drying and evaporating todryness. After chromatography on silica (eluant: ethyl acetate thenethyl acetate/methanol 9/1), 3.44 g of a mixture of the desiredsulfoxides were obtained.

STEP C:21-acetoxy-16-methylene-17α-hydroxy-Δ1,4,9(11)pregnatriene-3,20-dione

The product of Step B was dissolved in a mixture of 50 ml of toluene and50 ml of methanol and 2.68 g of triphenylphosphine were added. Themixture was heated at 85°-90° C. for 20 hours, then cooled and thesolvent was evaporated. After chromatography on silica (eluant:ether/dichloromethane/petroleum ether 4/1/5), 1.97 g of the expectedproduct were obtained melting at 213° to 215° C. (dec) aftercrystallization from methanol and having a specific rotation d[α]_(D)=-32.8° (C=10.5 mg/ml in chloroform)

IR Spectrum (cm⁻¹):

3200; 2900; 2850; 2250; 1750 (s); 1675(s); 1625; 1605; 1440; 1410; 1370;1235 (s); 1075; 915 (s).

NMR Spectrum ¹ H:

0.70(3H,s,Me-18); 1.41(3H,s,Me-19); 2.17(3H,s, COCH₃ ); 4.93 and 5.07(2H, AB system, J=17.6 Hz); 5.02(1][,s,c═CH₂); 5.15 (1H, s,c═CH₂);5.60(1H,massive, W_(1/2) =12 Hz, C₁₁ -H); 6.07(1H,massive, W_(1/2) =5Hz, C₄ -H); 6.29(1H,d-d, J=10.2 Hz, J=1.4 Hz,C₂ -H); 7.20(1H,d,J=10.2Hz, C₁ -H).

NMR Spectrum ⁻⁻ C:

even: 31.96(s); 32.25(s); 33.36(s); 35.05(s); 46.04(q); 45.45(q);68.65(s); 89.65(q); 114.45(s); 142.28(q); 152.64(q); 166.49(q);170.64(q); 186.37(q); 204.00(q).

odd: 14.18(p); 20.60(p); 26.81(p); 36.38(t); 46.31(t); 120.83(t);124.05(t); 127.50(t); 154.51(t).

EXAMPLE 521-acetoxy-16-methylene-Δ1,4,9(11)-pregnatriene-17α-ol-3,20-dione

205 mg of the mixture of Step A of Example 4 were dissolved in 3 ml ofdichloromethane and the mixture was cooled to -78° C. under a nitrogenatmosphere. 91 mg of metachloroperbenzoic acid at 80% were added andafter reacting for 2 hours, the starting product had completelydisappeared. 221 mg of triphenyl phosphine were added at low temperatureand then the dichloromethane was evaporated under reduced pressure. Itwas replaced by 3 ml of dry toluene and after 2 hours 30 minutes ofreflux, evaporation to dryness took place to obtain after purificationby chromatography on silica (eluant: cyclohexane/ether, 4/1 to 0/1), 113mg of the expected alcohol which was identical to that obtained inExample 4 and melted at 213° C. to 215° C.

EXAMPLE 621-acetoxy-16-methylene-Δ1,4,9(11)-pregnatriene-17α-ol-3,20-dione

648 mg of the disulfoxide of Example 3 were dissolved under an argonatmosphere in 10 ml of toluene and the solution was cooled to -60° C.500 mg of calcium carbonate were added and the reaction mixture washeated to 80° C. for 2 hours. Then, 540 mg of triphenylphosphine and 10ml of methanol were added. The solution was refluxed at 80° C. for 11hours, then cooled and evaporated to dryness. After chromatography onsilica (eluant: cyclohexane/ethyl acetate; 7/3 then 1/1), 217 mg of theexpected alcohol which was identical to that obtained in Example 4 andmelted at 213° C. to 215° C. were obtained.

EXAMPLE 6'21-acetoxy-16-methylene-Δ1,4,9(11)-pregnatriene-17α-ol-3,20-dione

287 mg of the disulfoxide of Example 3 or 3' were dissolved in 5 ml ofdry toluene and 250 mg of calcium carbonate were added. The solution wasrefluxed for 75 minutes and 1 equivalent of trimethylphosphite and 5 mlof methanol were added. Then 8 drops of trimethylphosphine were addedafter 8 hours and after 24 hours. After 34 hours of reflux, it wasobserved by thin layer chromatography that the reaction was complete.The solution was allowed to cool and then 15 ml of dichloromethane and15 ml of water were added. The mixture was filtered and the organic andaqueous phases were separated. The organic phase was washed with asaturated solution of sodium bicarbonate and a saturated solution ofsodium chloride. After drying and eliminating the solvent, 256 mg of thecrude expected product were obtained which was chromatographed on silica(eluant: petroleum ether/ethyl acetate 7/3 then 1/1) to obtain 64 mgwhich was 36% of the pure expected product which was identical to thatof Example 4 and melted at 213° C. to 215° C.

EXAMPLE 721-acetoxy-16-methylene-Δ1,4,9(11)-pregnatriene-17α-ol-3,20-dione

702 mg of the product of Example 1 were dissolved under a nitrogenatmosphere in 10.5 ml of dichloromethane and the solution was cooled to-60° C. 319 mg of metachloroperbenzoic acid at 80% were added and after30 minutes, another 243.6 mg of metachloroperbenzoic acid were added.The reaction stood between -60° C. and -40° C. for 5 hours and then 942mg of triphenylphosphine were added. The dichloromethane was evaporatedunder reduced pressure and was replaced by 11 ml of dry toluene. Thesolution was refluxed for 7 hours and after cooling, the solvent wasevaporated. The residue was chromatographed on a silica column (eluant:cyclohexane/ethyl acetate; 1/0 to 1/1 to obtain 115 mg of the expectedalcohol which was identical to that of Example 4 and melted at 213° C.to 215° C.

EXAMPLE 8 16-methylene-Δ4-pregnen-17α-ol-3,20 -dione STEP A:16α-[(phenylthio)-nitro-methyl]-Δ4-pregnen-3,20-dione

138 mg of Δ4,16-pregnadien-3,20-dione and 110 mg of(phenylthio)-nitro-methane were dissolved under an inert atmosphere andin the shade in 2 ml of a mixture (1--1) of tetrahydrofuran andtertiobutanol. Then 0.1 ml of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene)were added and the reaction mixture was stirred at ambient temperaturefor 48 hours. A solution of 0.5 g of citric acid in 5 ml of water wasadded and after extraction with dichloromethane, drying over sodiumsulfate, filtering and evaporating the solvent under reduced pressure,the residue was chromatographed on silica eluting with ether to obtain48.3 mg of the expected product in the form of a 2-1 mixture of epimersmelting at 166° C. to 172° C.

IR Spectrum (CHBr₃):

1702, 1660, 1551 cm⁻¹

NMR Spectrum (200 MHz):

¹ H: 7.4 (5H,m); 5.7 (1H,s); 5.4 (1H,2d); 3.55 (1H,m); 2.87 (1/3H,d,J-8.8Hz); 2.64 (2/3H,d, J=8.8Hz); 2.23 (2/33H,s); 2.16 (1/33H,s); 1.18(3H,s); 0.71 (3H,s).

¹³ C (ppm):

14.38; 17.47; 21.04; 28.72; 29.23; 31.58; 31.76; 32.64; 34.00; 35.39;35.83; 38.66; 38.76; 40.67; 45.23; 53.50; 54.75; 55.24; 66.86; 98.66;98.99; 124.26; 129.53; 129.80; 131.45; 132.94; 170.18; 199.19; 206.37.

STEP B: 16-methylene-Δ4-pregnen-17α-ol-3,20-dione

Using the procedure of Example 3, the product of Step A was reacted toobtain the corresponding disulfoxide which was converted as indicated inExample 6 to obtain the expected16-methylene-Δ4-pregnen-17α-ol-3,20-dione (obtained as indicated in U.S.Pat. No. 3,354,184).

EXAMPLE 9 3 β-acetoxy-16-methylene-Δ5-pregnen-17α-ol-3,20-dione STEP A:3 β-acetoxy-16α-[(phenylthio)-nitro-methyl]-Δ5-pregnen-20--one

124.3 g of 3 β-acetoxy-Δ5-, 16-pregnadien-20-one and 89.7 mg of(phenylthio)-nitro-methane were dissolved under an inert atmosphere andin the shade in 2 ml of a (1-1) mixture of tetrahydrofuran andtertiobutanol. Then, 0.05 ml of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene) were added and the reaction mixture was stirred atambient temperature for 48 hours. A solution 0.5 g of citric acid in 5ml of water was added and after extraction with dichloromethane, dryingover sodium sulfate and filtering, the solvent was evaporated underreduced pressure. The residue was chromatographed on silica eluted withan ether-petroleum ether (1-3) mixture to obtain 66 mg of the expectedproduct in the form of a 2-1 mixture of epimers.

IR Spectrum (CHBr₃):

1720, 1702, 1551 cm⁻¹

NMR Spectrum (200 MHz):

¹ H: (Δ)7.4 (SH,m); 5.35 (1H,2d); 4.6 (1H,m); 3.55 (1H,m); 2.85 (1/3H,d,J=8.8Hz); 2.64 (2/3H,d, J=8.8Hz); 2.23 (2/33H,s); 2.16 (1/33H,s); 2.04(3H,s); 1.02 (3H,s); 0.66 (3H,s).

¹³ C (ppm):

14.19; 19.32; 20.88; 21.46; 27.72; 29.36; 31.53; 36.58; 36.96; 38.04;38.72; 40.46; 45.19; 49.64; 55.34; 55.83; 66.90; 73.74; 98.73; 99.06;121.96; 129.43; 129.71; 132.88; 139.72; 170.56; 206.64.

STEP B: 3 β-acetoxy-16-methylene-Δ5-pregnen-17-ol-3,20-dione

Using the procedure of Example 3, the product of Step A was reacted toobtain the corresponding disulfoxide which was converted as indicated inExample 6 to obtain 3 β-acetoxy-16-methylene-Δ5-pregnen-17α-ol-20-one(described in U.S. Pat. No. 3,519,619).

EXAMPLE 10 16-methylene-Δ4,9(11)-pregnadiene-17α-ol-3,20-dione STEP A:16α-[(phenylthio)-nitromethyl-Δ4,9(11)pregnadien-3,20-dione

100 mg of Δ4,9(ll)-pregnatrien-3,20-dione and 100 mg of(phenylthio)-nitro-methane were dissolved under an inert atmosphere andin the shade in 1 ml of a (1--1) mixture of tetrahydrofuran andtertiobutanol. Then, 30 mg of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene)were added and the reaction mixture was stirred at ambient temperaturefor 16 hours. A solution of 0.5 g of citric acid in 5 ml of water wasadded and after extraction with dichloromethane, drying over sodiumsulfate and filtering, the solvent was evaporated under reducedpressure. The residue was chromatographed on silica eluting with apetroleum ether-ethyl acetate mixture (2-1) to obtain 129 mg of theexpected product in the form of a 2-1 mixture of epimers.

IR Spectrum (CHBr₃):

1707, 1665, 1614, 1552 cm⁻¹

NMR Spectrum (200 MHz):

¹ H: (Δ) 7.4 (5H,m); 5.75 (1H,s); 5.55 (1H,m); 5.4 (1H, 2d); 3.6 (1H,m);2.95 (1/3H,d, J=9Hz); 2.75 (2/3H,d, J=9Hz); 2.24 (2/3H,s); 2.17(1/3H,s); 1.34 (3H,s); 0.65 (3H,s).

¹³ C (ppm):

13.96; 26.16; 29.50; 30.08; 31.28; 31.98; 32.60; 33.90; 34.25; 36.94;40.70; 41.07; 43.30; 43.47; 51.58; 52.09; 66.50; 66.68; 98.46; 98.81;117.84; 124.26; 129.41; 129.70; 132.81; 145.10; 198.7; 206.03.

STEP B: 16-methylene-Δ4,9(11)-pregnadien-17α-ol-3,20-dione

Using the procedure of Example 3, the product of Step A was reacted toobtain the corresponding disulfoxide which was converted as indicated inExample 6 to obtain the expected16-methylene-Δ4,9(11)-pregnadien-17α-ol-3,20-dione (described in U.S.Pat. No. 3,359,287).

Various modifications of the compounds and method of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What is claimed is:
 1. A process for the preparation of a compound ofthe formula ##STR25## in which ##STR26## is either a 3-keto-Δ4-system or3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄ is hydrogen or aprotector group of hydroxy, R is methyl, --CH₂ OH or --CH₂ OR', in whichR' is a group of hydroxy, R₂ and R₃ are hydrogen or R₂ is fluorine andR₃ is formyloxy or acetyloxy and the dotted lines in position 9(11)indicate the optional presence of a second bond comprising reacting acompound of the formula ##STR27## in which K, R, R₁, R₂, R₃ and thedotted lines are defined as above and R₁ and R'₁ are individuallyselected from the group consisting of methyl, a branched alkyl of 5 to 8carbon atoms not possessing hydrogen in the β position, aryl of up to 10carbon atoms, heteroaryl of up to 10 carbon atoms and at least oneheteroatom selected from the group consisting of nitrogen, sulfur andoxygen and benzyl, n and m are individually the numbers of 0 or 1 withat least two equivalents of an oxidizing agent to obtain a compound ofthe formula ##STR28## and subjecting the latter hot to the action of athiophilic agent to obtain the expected compound of formula A.
 2. Theprocess of claim 1 wherein the thiophilic agent is peracid or hydrogenperoxide.
 3. The process of claim 1 wherein the oxidizing agent is aperacid or hydrogen peroxide.
 4. A process for the preparation of acompound of the formula ##STR29## in which ##STR30## is either a3-keto-Δ4-system or 3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄is hydrogen or a protector group of hydroxy, R is methyl, --CH₂ OH or--CH₂ OR', in which R' is a protector group of hydroxy, R₂ and R₃ arehydrogen or R₂ is fluorine and R₃ is formyloxy or acetyloxy and thedotted lines in position 9(11) indicate the optional presence of asecond bond comprising reacting a compound of the formula ##STR31## iwhich K, R, R₁, R'₁, R₂, R₃ and the dotted lines are defined as aboveand R₁ and R'₁ are individually selected from the group consisting ofmethyl, a branched alkyl of 5 to 8 carbon atoms not possessing hydrogenin the β position, aryl of up to 10 carbon atoms, heteroaryl of up to 10carbon atoms and at least one heteroatom selected from the groupconsisting of nitrogen, sulfur and oxygen and benzyl, n and m areindividually the numbers 0 or 1 hot with a thiophilic agent to obtainthe expected compound of formula A.
 5. A process for the preparation ofa compound of the formula R ##STR32## in which ##STR33## is either a3-keto-Δ4-system or 3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄is hydrogen or a protector group of hydroxy, R is methyl, --CH₂ OH or--CH₂ OR', in which R' is a protector group of hydroxy, R₂ and R₃ arehydrogen or R₂ is fluorine and R₃ is formyloxy or acetyloxy and thedotted lines in position 9(11) indicate the optional presence of asecond bond comprising reacting a compound of the formula ##STR34## inwhich K, R, R₂ and R₃ are defined as above and R₁ and R'₁ areindividually selected from the group consisting of methyl, a branchedalkyl of 5 to 8 carbon atoms not possessing hydrogen in the β position,aryl of up to 10 carbon atoms, heteroaryl of up to 10 carbon atoms andat least one hetero-atom selected from the group consisting of nitrogen,sulfur and oxygen and benzyl, n and m are individually the numbers 0 or1 by heating with a thiophilic agent to obtain a compound of the formula##STR35## in which K, R, R'₁, R₂ R₃ and the dotted lines have the abovemeaning, the dolled lines in position 16 (17) and 16(16') represents avinyl and allyl sulfide mixture and the wavy line represents an isomermixture, reacting the latter with at least one equivalent of anoxidizing agent to obtain a compound of the formula ##STR36## in whichK, R, R'₁, R₂ R₃ the dotted lines and the wavy line have the abovemeaning and reacting the latter hot with a thiophilic agent to obtainthe expected compound of formula A.
 6. A process for the preparation ofa compound of the formula ##STR37## in which ##STR38## is either a3-keto-Δ4-system or 3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄is hydrogen or a protector group of hydroxy, R is methyl, --CH₂ OH or--CH₂ OR', in which R' is a protector group of hydroxy, R₂ and R₃ arehydrogen or R₂ is fluorine and R₃ is formyloxy and acetyloxy and thedotted liens in position 9(11) indicate the optional presence of asecond bond comprising reacting a compound of the formula ##STR39## inwhich K, R, R₁, R'₁, R₂, R₃ and the dotted lines are defined as aboveand R₁ and R'₁ are individually selected from the group consisting ofmethyl, a branched alkyl of 5 to 8 carbon atoms not possessing hydrogenin the β position, aryl of up to 10 carbon atoms, heteroaryl of up to 10carbon atoms and at least one heteroatom selected from the groupconsisting of nitrogen, sulfur and oxygen and benzyl, n and m areindividually the numbers 0 or 1 with at least two equivalents of anoxidizing agent to form a compound of the formula ##STR40## and reactingthe latter hot with a thiophilic agent to obtain a compound of formulaA.
 7. A process for the preparation of a compound of the formula##STR41## in which ##STR42## is either a 3-keto-Δ4-system or3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄ is hydrogen or aprotector group of hydroxy, R is methyl, --CH₂ OH or --CH₂ OR', in whichR' is a protector group of hydroxy, R₂ and R₃ are hydrogen or R₂ isfluorine and R₃ is formyloxy or acetyloxy and the dotted lines inposition 9(11) indicate the optional presence of a second bondcomprising reacting a compound of the formula ##STR43## in which K, R,R₁, R'₁, R₂, R₃ and the dotted lines are defined R₁ and R'₁ areindividually selected from the group consisting of methyl, a branchedalkyl of 5 to 8 carbon atoms not possessing hydrogen in the β position,aryl of up to 10 carbon atoms, heteroaryl of up to 10 carbon atoms andat least one heteroatom selected from the group consisting of nitrogen,sulfur and oxygen and benzyl, n and m are individually the numbers 0 or1 hot with thiophilic agent to obtain the expected compound of formulaA.
 8. A process for the preparation of a compound of the formula##STR44## in which ##STR45## is either a 3-keto-Δ4-system or3-keto-Δ1,4-system or a 3-OR₄ -Δ5-system in which R₄ is hydrogen or aprotector group of hydroxy, R is methyl, --CH₂ OH or --CH₂ OR', in whichR' is a protector group of hydroxy R₁ and R'₁ are individually selectedfrom the group consisting of methyl, a branched alkyl of 5 to 8 carbonatoms not possessing hydrogen in the β position, aryl of up to 10 carbonatoms, heteroaryl of up to 10 carbon atoms and at least one heteroatomselected from the group consisting of nitrogen, sulfur and oxygen andbenzyl, n and m are individually the numbers 0 or 1, R₂ and R₃ arehydrogen or R₂ is fluorine and R₃ is formyloxy or acetyloxy and thedotted lines in position 9(11) indicate the optional presence of asecond bond comprising reacting a compound of the formula ##STR46## inwhich K, R, R₂, R₃ and the dotted lines have the above definition in abasic medium with a compound of the formula

    R.sub.1 S--CH.sub.2 --NO.sub.2

in which R₁ has the above meaning to obtain a compound of the formula##STR47## in which K, R, R₁, R₂, R₃ and the dotted lines have the abovemeaning, reacting the latter in the presence of an acid with a thiol ora thiophenol of the formula

    HS--R'.sub.1

in which R'₁ has the above definition to obtain a compound of the##STR48## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lines have theabove definition, optionally reacting the latter either with anequivalent of an oxidizing agent to obtain a compound of the formula##STR49## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lines have theabove definition or with at least two equivalents of an oxidizing agentto obtain a compound of the formula ##STR50## in which K, R, R₁, R'₁,R₂, R₃ and the dotted lines have the above definition.
 9. The process ofclaim 8 comprising reacting a compound of the formula ##STR51## in whichK, R, R₂, R₃ and the dotted lines have the meaning of claim 8, in abasic medium with a compound of the formula

    R.sub.1 S--CH.sub.2 --NO.sub.2

in which R₁ has the meaning of claim 8, to obtain a compound of theformula ##STR52## in which K, R, R₁, R₂, R₃ and the dotted lines havethe definition of claim 8, reacting the latter in the presence of anacid with a thiol or a thiophenol of the formula

    HS--R'.sub.1

in which R'₁ has the definition of claim 8 to obtain a compound of theformula ##STR53## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lineshave the definition of claim 8, reacting the latter with at least twoequivalents of an oxidizing agent to obtain a compound of the formula##STR54## in which K, R, R₁, R'₁, R₂, R₃ and the dotted lines have thedefinition of claim
 8. 10. The process of claim 8 wherein the reactionof the compound of formula P and the compound of formula II is carriedout in the presence of an amino base; the action of the thiol or thethiophenol is catalyzed by a carboxylic acid and the oxidizing agent isperacid or hydrogen peroxide in the presence of a carboxylic acid.